Open AccessThe FZD 7‐ TWIST 1 axis is responsible for anoikis resistance and tumorigenesis in ovarian carcinoma
Author(s) -
Tan Ming,
Asad Mohammad,
Heong Valerie,
Wong Meng Kang,
Tan Tuan Zea,
Ye Jieru,
Kuay Kuee Theng,
Thiery Jean Paul,
Scott Clare,
Huang Ruby YunJu
Publication year - 2019
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12425
Subject(s) - twist transcription factor , biology , wnt signaling pathway , frizzled , microbiology and biotechnology , carcinogenesis , anoikis , phenotype , genetics , signal transduction , cancer cell , epithelial–mesenchymal transition , gene , cancer , downregulation and upregulation
Frizzled family receptor 7 ( FZD 7 ), a Wnt signaling receptor, is associated with the maintenance of stem cell properties and cancer progression. FZD 7 has emerged as a potential therapeutic target because it is capable of transducing both canonical and noncanonical Wnt signals. In this study, we investigated the regulatory pathway downstream of FZD 7 and its functional roles. We found that FZD 7 expression was crucial to the maintenance of the mesenchymal phenotype, anoikis resistance, and spheroid and tumor formation in ovarian cancer (OC). We identified TWIST 1 as the crucial downstream effector of the FZD 7 pathway. TWIST 1 , a basic helix loop helix transcription factor, is known to associate with mesenchymal and cancer stem cell phenotypes. Manipulating TWIST 1 expression mimicked the functional consequences observed in the FZD 7 model, and overexpression of TWIST 1 partially rescued the functional phenotypes abolished by FZD 7 knockdown. We further proved that FZD 7 regulated TWIST 1 expression through epigenetic modifications of H3K4me3 and H3K27ac at the TWIST 1 proximal promoter. We also identified that the FZD 7 ‐ TWIST 1 axis regulates the expression of BCL 2 , a gene that controls apoptosis. Identification of this FZD 7 ‐ TWIST 1 ‐ BCL 2 pathway reaffirms the mechanism of anoikis resistance in OC. We subsequently showed that the FZD 7 ‐ TWIST 1 axis can be targeted by using a small molecule inhibitor of porcupine, an enzyme essential for secretion and functional activation of Wnts. In conclusion, our results identified that the FZD 7 ‐ TWIST 1 axis is important for tumorigenesis and anoikis resistance, and therapeutic inhibition results in cell death in OCs.